Comparative systematic genetics for cardiovascular disease gene identification

描述（由申请人提供）：该提案将导致识别增加患心血管疾病风险的基因变异。潜在的假设是，在模式生物中进行的系统遗传学使疾病特异性基因模块的识别成为可能。这一假设将在第一阶段通过以下目标进行测试：(1)创建一个在酵母、蠕虫、苍蝇、斑马鱼和其他模式生物中进行的系统遗传筛选中观察到的表型数据库。(2)开发并应用数据挖掘算法，以识别其缺失或沉默表型在模式生物中显示相似模式的基因模块。(3)识别与心血管疾病相关的已知变异基因富集的模块。然后，这些模块中的其他基因将成为赋予心血管疾病风险的变异的候选基因，或可用于改善全基因组关联测试的先验。在II期，候选基因的变异将在心血管患者群体中进行基因分型，目的是确定遗传标记，以协助心血管疾病的诊断和治疗。如果成功，这一提议将导致基因测试，这将改善心血管疾病风险患者的临床治疗。开发的比较系统遗传学平台将广泛适用于识别与其他人类疾病相关的基因模块，并将扩展到为越来越多的模式生物收集的系统遗传学数据。

DESCRIPTION (provided by applicant): This proposal will lead to identification of gene variants that increase the risk of developing cardiovascular disease. The underlying hypothesis is that systematic genetics conducted in model organisms enables the identification of disease-specific gene modules. This hypothesis will be tested in Phase I through the following Aims: (1) Create a database of phenotypes observed in systematic genetic screens conducted in yeast, worm, fly, zebrafish, and other model organisms. (2) Develop and apply data mining algorithms to identify modules of genes whose deletion or silencing phentoypes show similar patterns across model organisms. (3) Identify modules that are enriched for genes with known variants relevant to cardiovascular disease. Other genes in these modules will then be candidate genes for variants conferring cardiovascular disease risk or can be used to improve priors for whole-genome association tests. In Phase II, variants of candidate genes will be genotyped across a cardiovascular patient population with the goal of identifying genetic markers to assist in diagnosis and treatment of cardiovascular disease. If successful, this proposal will lead to genetic tests that will improve the clinical treatment of patients at risk for cardiovascular disease. The comparative systematic genetics platform developed will be broadly applicable to identifying gene modules relevant to other human diseases and will extend to systematic genetics data collected for a growing set of model organisms.